Different protection of K252a and N-acetyl-L-cysteine against amyloid-beta peptide-induced cortical neuron apoptosis involving inhibition of MLK3-MKK7-JNK3 signal cascades.
Amyloid-beta peptide (Abeta) has been implicated in the etiopathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms underlying Abeta neurotoxicity remain to be elucidated. This study showed that Abeta treatment resulted in the increased phosphorylation (activation) of MLK3, MKK7, and JNK3 in cultured cortical neurons, which characterized as biphasic activation (first peaked at 1 hr and second peaked at 12 hr after Abeta treatment). K252a blocked Abeta-induced neuronal apoptosis, both early and late phases of MLK3-MKK7-JNK3 activation, as well as downstream signal events involving p-JNKs nuclear translocation, c-Jun phosphorylation, and Bad translocation to the mitochondria. The neuroprotective effect of K252a on Abeta-induced apoptosis was partially dependent on Akt activation. In contrast, antioxidant N-acetyl-L-cysteine (NAC) reduced early, but not late, MLK3-MKK7-JNK3 activation by Abeta treatment and provided a weak neuroprotective ability in Abeta-induced apoptosis. Taken together, Abeta neurotoxicity is mainly due to MLK3-MKK7-JNK3 signal cascades. The late signal events of MLK3 activation after Abeta treatment may play an important role in AD neuronal loss and will be a promising pharmacological target for AD therapeutic intervention.
Xu
Yan
Y
Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu, China.
Hou
Xiao-Yu
XY
Liu
Yong
Y
Zong
Yan-Yan
YY
D000111:Acetylcysteine / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D026121:Indole Alkaloids / Q000494:pharmacology*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D000111:Acetylcysteine; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002227:Carbazoles; D026121:Indole Alkaloids; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D048057:Mitogen-Activated Protein Kinase 10; D018696:Neuroprotective Agents; D051057:Proto-Oncogene Proteins c-akt; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C049985:staurosporine aglycone